Malignant Hyperthermia (MH) is an anesthetic reaction that occurs in certain individuals during surgery. In this syndrome certain anesthetic agents and depolarizing muscle relaxants trigger a rise in body temperature and muscle spasm (rigidity). The result can be fatal. The precise aetiology of this syndrome is unknown and the metabolic changes that occur during the acute response have not been described adequately. The systematic study of MH requires the use of a suitable animal model and for this a purebred strain of MH Pietrain pigs will be used. The biochemical experiments that are proposed in this project will test the hypothesis that calcium regulation is defective in MH muscle. It follows that sarcoplasmic ionized calcium concentration would be abnormally elevated during MH crisis. The project proposes to determine whether the regulation of calcium by the sarcolemma and T-tubule membranes is abnormal in MH muscle. Calcium regulation by these membranes will be determined using isolated sarcolemma and T-tubule vesicles derived from control and MH muscle. In addition, the biochemical changes that are responsible for some of the features of MH crisis will be defined. This will be determined using isolated muscle strips that can be prefused with different anaesthetics and Mh-triggering or blocking drugs. Possible modifications in the calcium permeability of non-muscle cell membranes will also be examined in these MH pigs using red blood cell membranes. These different approaches should provide a description of the molecular defect(s) responsible for the onset of MH crisis. An understanding of the nature of this disease will be of great assistance in the future identification, management of patients, and treatment of MH crisis. In addition the results should lead to the development of a reliable test for MH individuals that does not involve surgical intervention. Furthermore, the results should provide basic information regarding the regulation of calcium by both muscle and non-muscle membranes. This understanding will be important in the future elucidation of the mechanisms of many other muscle diseases in which calcium metabolism is abnormal.